Hypersensitivities result from our immune system overreacting. Our police department is restless and impossible to calm down. How does the immune system lose control and how can it be tamed?
Allergies, or hypersensitivities, are daily triggered by allergens. Different forms of allergies exist and depend on several factors that lead the disease onset (see the article Help me doctor, I am allergic!. But a classification of hypersensitivities also exists depending on their type of mechanisms.
The immune mechanisms involved in allergies
There are different types of hypersensitivities, which include immediate (type I), cytotoxic (type II), antibody mediated (type III) and delayed hypersensitivity (type IV). IgE mediated allergies, also called immediate hypersensitivities, take place in two phases. First, a sensitization phase to a substance (allergen) takes place, then a revelation phase. It is as though a quiet and peaceful people (allergen) who had an alliance with our kingdom (the body) were suddenly targeted as an enemy that we should be very suspicious of. After a while, someone from our police department sees the proclamation in the archives and marks them as dangerous, resulting in our army (the immune system) attacking them without needing any justification (see the article Immune system ‘s G.I. in action).
The shining star of all immune cells in hypersensitivities are mast cells. The sensitization phase does not induce a reaction yet and goes by undetected. The allergen penetrates the body and is captured by the dendritic cells which send the information about the “enemy” to our army. Originating from B cells under the proper stimulating environment containing cytokines IL-4 and IL-13, the plasmocytes produce IgE (type E immunoglobulin). These are later fixed on mast cells localized at the allergen entrance site. During the revelation phase, when the second contact with the allergen occurs, it will be trapped on IgE present at the mast cells surface. This will lead to a release of inflammation proteins and to the recruitment of other immune cells. Upon each further contact with the allergen, there will be an acute and maladjusted reaction from the body.
Figure 1: Immune mechanism from type E allergies (Adapted from Evrard B.,2020, Pages 20-31.)[ZB6]
Another immune mechanism, independent of IgE, exists in delayed hypersensitivity and is related to contact allergies. It happens when an accumulation of proteins cause the formation of a hapten. This build-up of proteins, in association with other proteins from the skin, triggers an immune response that uses different mechanisms that the type I hypersensitivity. The T cells that have been stimulated are mainly accountable for the inflammation response and will recruit macrophages. This response could also lead to a tissue lysis mediated by cytotoxic T cells. Delayed hypersensitivity is also implicated with auto-immune diseases such as type 1 diabetes and inflammatory diseases like Crohn’s disease. The other types of hypersensitivity (types II and III) are rare and don’t cause allergies but rather auto-immune diseases.
Immune cells in allergies
Some people produce a disproportioned amount of IgE antibodies in response to a very scarce quantity of allergens (see the article Help me doctor, I am allergic!). Cells harboring IgE receptors at their membrane surface, mainly mast cells and basophiles, are involved in allergies. Other cells, like ILC2, have been recently highlighted in allergies, with all the other classical immune cells, such as dendritic cells and adaptive immune cells are still implicated in allergies. The immune response is the foundation of the immune system and has been described previously in the article Immune system ‘s G.I. in action.
The mast cells are known to be involved in allergies. They are a part of the innate immunity, and their role is to protect the body from external pathogens. They are involved in the maturation of specific cells such as IL-33, called alarmins. Alarmins are released as an alarm system to recruit other inflammation cells. Mast cells have granules that hold different molecules that are released at separate times. First, inflammatory response molecules such as TNFα, IL-4 and histamine dilate the blood vessel, induce the swelling of the inflamed area, and trigger the recruitment of other immune cells. Later on, IL-10 and TGFβ help resolve the inflammation and activate the tissue remodeling. Mast cells do not travel in the blood but are rather localized around the area in contact with the body exterior. They have IgE receptors (FcεRI) which, once triggered by allergens, are the key event of acute allergies.
Basophiles are also part of the innate immunity and are involved in allergies. Same as mast cells, they release histamine and IL-4 but they especially release heparin for vasodilation and production of IgE. They also exhibit IgE receptors at their membrane surface and, contrary to mast cells, they can travel through the bloodstream.
Everybody knows the Th2 T-cells in adaptive immunity but lesser known are ILC2, their equivalent in innate immunity. These cells are, once again, localized near contact areas with the external environmentand have alarmin receptors. They are specialized in immune response type 2 that occurs during allergies. They can produce IL-4 and, most importantly, IL-13 which triggers the production of IgE by plasmocytes. ILC2 take a great part in allergies phenomenon such as asthma or food allergies mediated by IgE.
Figure 2: Immune cells involved in allergies. (Adapted from Holtzman MJ, et al. Nat Rev Immunol 2014;14:686– 98.)
Diagnosis and treatments of allergy
Allergy diagnosis is firstly a discussion with an allergist to know the patient’s general habits. When an allergy is suspected, the patient goes through a deeper battery of tests. The prick-tests are done on the forearm with a drop of several allergens and a subcutaneous sting through the skin in the tested area. The patch-test is to identify the IgE nondependent cutaneous allergies. If we are still not sure about the type of allergies, the doctor will do a serological test to identify IgE specific to allergens. Finally, for the trickiest allergies such as food or drug allergies, there are the provocation tests which are performed under medical supervision at the hospital.
The first line of action against allergies are the eviction of food allergies, controlling the sanitary environment in case of dust mites, and to be aware of the pollen timetables. Drug therapies often treat the symptoms but not the allergy itself. Antihistaminic and corticoids are efficient but could trigger a lot of side effects. There are bronchodilator and antibody against IgE for asthma treatment. Recently, immunotherapies have been developed for allergies that focus on desensitization. It is an allergen immunotherapy that presents itself as a vaccination against specific allergens. The treatment formats are either by subcutaneous injection or by oral pill intake with spaced out and increased doses of allergens. The purpose is to acclimate the immune system to the presence of allergens to trigger the production of specific T-reg cells and in this way create a tolerance to these allergens.
Figure 3: Allergen immunotherapy. (Adapted from DOI: https://doi.org/10.1016/j.jaci.2017.08.025.)
Hypersensitivities are exaggerated responses from the immune system which provoke inflammation and cellular lysis that jeopardize the body’s integrity. Innate and adaptive immune cells are both involved in those pathologies. Type 1 hypersensitivity, mediated by IgE and mast cells, is accountable for most of allergies. There are numerous drugs which could diminish the symptoms, but immunotherapies are actually developed to educate the immune system to tolerate allergens.
Article written by Anne Clerico
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